The present invention relates to an improved process for the preparation of arteether. Arteether is an ethyl ether derivative of dihydroartemisinin. The dihydroartemisinin is derived from artemisinin, which is a unique sesquiterpene lactone isolated from the plant Artemisia annua. Arteether prepared for the process of the invention is useful for the treatment of uncomplicated/severe complicated/cerebral and multi-drug resistant malaria.
Approximately, 300-400 million people world wide now suffer from malaria, and each year 1-3 million (mostly children) die from this infectious disease. The rapidly spreading multi-drug resistance of parasite to standard quinoline based antimalarial drugs such as chloroquine and mefloquine complicates chemotherapy treatment of malarial patients. A new class of non-alkaloidal antimalarial compounds artemisinin (derived from Artemisia annua) and its semi-synthetic derivatives, artemether, arteether and artesunate as well as promising artelinic acid are increasingly being used for the treatment of uncomplicated/severe complicated/cerebral and multi-drug resistant malaria.
Arteether is a totally new drug introduced in India and has under gone extensive preclinical, animal, toxicological studies as well as clinical studies in Indian subjects as per drug regulatory requirements. Arteether is an ideal antimalarial drug especially for treating drug resistant and complicated P. falciparum malaria. Arteether show rapid schizontocidal action with quicker parasite clearance rate and short fever clearance time, virtually with no side effects and low recrudescence rate.
Brossi, et al (Brossi A; Vengopalan, B.; Dominguez Gerpe, L; Yeh, H. J. C.; Flipper-Anderson, J. L. Buchs, P; Luo, X. D.; Miehous, W and Peters, W. J. Med. Chem. 31, 646-649, 1988) report the isolation of arteether by dissolving dihydroartemisinin in a solvent mixture of benzene and ethanol by heating the solution at 45xc2x0 C., followed by addition of BF3-etherate and reaction mixture was refluxed at 70xc2x0 C. for 1 hr. The reaction mixture was washed with 10% sodium acetate solution and extracted by dichloromethane, dried over anhydrous sodium sulphate followed by evaporation yielded xcex1, xcex2 mixture of arteether and some side products. Chromatography of the reaction product was done to remove some impurities formed during the reaction.
EL-Feraly et al (F. EL-Feraly, M. A. Al-yahYa, K Y. Orabi, D. R. McPhail and A. T. McPhail J. Nat. Prod. 55, 878-883,1992) report the preparation of arteether by a process in which anhydrodihydroartemisinin, prepared from the artemisinin, was dissolved in absolute alcohol. The reaction mixture was stirred in presence of p-toluene sulphonic acid used as a catalyst. Upon workup, it yielded a mixture of xcex2 arteether and C-11 epimer in the ratio 3:1. In this process, only xcex2 arteether is obtained and separation of its C-11 epimer is difficult and preparation of anhydrodihydroartemisinin is a tedious process. The reaction took 22 hours to complete. The Lewis acid catalyst used in this reaction is required in large amount (60 mg acid catalyst by 100 mg anhydrodihydroartemisinin).
Another method is reported by Bhakuni et al. (Bhakuni R. S; Jain D. C and Sharma, R P., Indian J. Chemistry, 34B, 529-30 (1995). Arteether was prepared by dissolving dihydroartemisinin in alcohol and benzene mixture and then adding chlorotrimethylsilane as acid catalyst. The reaction was stirred for 2 hrs. at room temperature. The reaction mixture was washed with 10% sodium acetate solution and workup as usual method. The other products formed during the reaction were removed by column chromatography, to obtain pure arteether.
Another method is reported by Lin et al. (A. J Lin and R. E. Miller. J. Med. Chem. 38, 764-770 1995), in which the new ether derivatives were prepared by dissolving dihydroartemisinin in anhydrous ether and adding appropriate alcohol followed by boron trifluoride etherate. The reaction mixture was stirred at room temperature for 24 hrs. The yield of purified products ranged from 40-90%. Purification was achieved by the use of silica gel chromatography.
The above methods suffer from some disadvantages. Benzene is used as solvent, which on work up left a few non-volatile impurities in the reaction product. Also, the use of benzene as a solvent is not acceptable in Europe due to its carcinogenic nature. The minor products formed during the reaction require separation by column chromatography, thereby causing loss of arteether yield.
It is an object of the invention to provide an improved process for the preparation of arteether by replacing benzene as a solvent.
It is another object of the invention to obtain pure arteether without requiring chromatography to separate minor by-products.
It is a further object of the invention to replace the liquid acid catalyst used in the prior art by a solid acid catalyst.
It is a further object of the invention to provide a process the preparation of arteether wherein the quantity of solid acid catalyst required is also minimised.
It is another object of the invention to reduce the reaction time and temperature conditions for the isolation process.
It is another object of the invention to provide an improved process for the preparation of arteether which results in higher yield with 30:70 ratio of xcex1-xcex2-isomers of arteether in the reaction product.
It is another object of the invention to provide an improved process for the preparation of arteether from dihydroartemisinin that is cost effective and economical.
The present invention provides a process for the preparation of arteether from dihydroartemisinin, which comprises dissolution of dihydroartemisin in alcohol and adding a solid acid catalyst along with trialkylorthoformate in the reaction mixture, which produce higher yield of arteether, without chromatography. The solid acid catalyst can be reused in the process.
Accordingly, the present invention provides an improved process for the preparation of arteether, which comprises:
(a) dissolving dihydroartemisinin in dry ethanol;
(b) adding a solid acid catalyst with trialkylorthoformate in the reaction mixture;
(c) stirring the reaction mixture at room temperature for a period ranging from 1 to 10 hours;
(d) adding H2O to the reaction mixture and extracting the reaction product with a non-polar organic solvent, and
(e) drying the solvent in step (d) above over anhydrous sodium sulphate and evaporating the solvent to obtain pure arteether.
In an embodiment of the present invention, the sold acid catalyst is selected from p-toluenesulphonic acid, anhydrous AlCl3 and cation exchange resins.
In a further embodiment of the invention, the dihydroartemisinin and the solid acid catalyst are used in a ratio of 1-2:1 w/w.
In another embodiment of invention, the trialkylorthoformate is selected from triethylorthoformate, trimethylorthoformate and other trialkylorthoformate.
In a further embodiment of the invention, the dihydroartemisinin and the trialkylorthoformate are used in the ratio of 10-25:1.
In another embodiment of the invention, ethanol is used as a solvent and the reactant.
In another embodiment of the invention, the reaction product is stirred at a temperature ranging between 20-40xc2x0 C. and the ratio of xcex1 and xcex2 arteether isomers obtained in the reaction product is xcex1:xcex2 arteether=20-30:80-70.
In another embodiment of the invention, the solid acid catalyst cation exchange resin can be regenerated and reused in the reaction.
In the process of the invention, dihydroartemisinin is dissolved in absolute ethanol rather than benzene or anhydrous ether. In prior art processes, dihydroartemisinin was dissolved in the solvent benzene, which resulted in non-volatile impurities remaining in the product arteether after completion of reaction and work up. Benzene is also reported to be a carcinogenic in nature and is banned in some European countries. In the process of the invention, the ethanol used acts both as solvent and reactant.
The solid acid catalyst used in the process of the invention increases the purity of arteether. Prior art processes use liquid acid catalyst, which contain some impurities and are difficult to purify. The addition of reagent triethylorthoformate in the process of the invention reduces the quantity of acid catalyst required and the time of completion of the reaction at room temperature.
Another advantage of the reagent is that the reaction is completed at room temperature, without forming any side products whereas in the previous methods reaction mixture had to be heated up to 70xc2x0 C. for 1-2 hrs resulting in the production of side products in the reaction.
As the reaction is carried under room temperature and no side products are formed, there is no need of chromatography for the purification of the product. This results in arteether being obtained in higher yield due to no loss of starting material in the formation of side products. Also the need for chromatography is avoided. The work up of reaction is simple as it comprises only extraction of reaction product with non-polar solvent and drying over sodium sulphate and evaporation under vacuum. The arteether is obtained in pure form and is not contaminated with the impurities of benzene and other solvents. The cation exchange resin used in the reaction as acid catalyst economises the preparation of reaction product as the resin is recovered by filtration of reaction product and can be reused. The pure arteether was obtained by drying and evaporation of organic solvent. The process of the invention provides pure and high yield of arteether. The two isomers of arteether obtained in the reaction are in the ratio of 30:70 (+5%).
The improvement in the process for the preparation of arteether from dihydroartemisinin comprises i), dissolution of dihydroartemisinin in ethanol, ii), stirring the solution for 10 min at room temperature iii), addition of triethylorthoformate and acid catalyst in the reaction mixture iv), followed by further stirring of the reaction mixture at room temperature v) addition of water and non polar solvent in the reaction mixture and finally, the organic solvent is dried over anhydrous sodium sulphate, evaporation of the reaction mixture yield the pure arteether.
The invention further provides a method for the preparation of different arteethers using different trialkylorthoformate and alcohols.